Kidneys are two bean-shaped organs, each about the size of your fists. They are located near the middle of your back, just below the rib cage. Inside each kidney about a million tiny structures called nephrons filter blood. They remove waste products and extra water, which become urine. The kidneys function on body fluid by filtering a substantial volume of blood (about one-fifth of the total cardiac output is pumped directly to the kidneys). This specific volume of blood is known as the “renal fraction”. Approximately, 1.2 liters of blood flows through the kidneys in adult males. As the blood passes through the kidneys, the nephrons clear the blood plasma of unwanted substances such as urea, creatinine, uric acid etc. Most kidney diseases attack the nephrons and this damage may lead to inability in the removal of wastes. Thus, a kidney will become damaged and thus diminish or even cease its function of clearing the blood. The prevalence of kidney diseases is increasing dramatically. Various renal function tests have been devised to assist a physician to evaluate the extent and type of kidney damage that has occurred.
Also, these renal function tests are useful in evaluating whether a kidney is operating properly following a kidney transplant operation. Imaging techniques such as magnetic resonance imaging (MRI), X-rays, or ultrasound (US) provide valuable information on anatomy (namely, anatomical structural imaging), but give limited information on metabolic, biochemical or molecular events.
Nuclear medicine products such as diagnostic radiopharmaceuticals have been in use in very small concentrations at a tracer level in which pharmacological effects are ruled out. Nuclear medicine has been used for more than five decades, and there are no unknown long-term adverse effects from such low-dose exposure. One such renal function testing procedure is known as intravenous scintigraphic urography (this procedure is also commonly known as a dynamic renal function imaging study). Historically, I-131-ortho iodohippuran (131I-OIH) has been used for more than 45 years in the nuclear medicine for kidney function determination studies as a Renal Tubular Secretion agent. Due to the high energy of 364 KeV photon flux, one would experience a significant scatter of the images makes it un-suitable for proper diagnoses in the diseased state of the organ. In addition, an 8 day half-life of I-131 radioisotope coupled with the high energy makes 131I-OIH inadequate for kidney function determination for pediatric usage solely due to high radiation dose to the children. Furthermore, I-131 emits beta particle during radioactive decay which can cause damage to surrounding tissue.
There are several Tc-99m labeled organic molecule based radiopharmaceuticals existed in the literature for renal function both as tubular secretion agents and Glomerular Filtration Rate (GFR) marker agents (Fritzberg et al., U.S. Pat. No. 4,980,147; Fritzberg, et al., J. Nucl. Med. 1986, 27, 111-116). These radiopharmaceuticals include, Tc-99m (Diethylene Triamine Penta Acetic acid (Tc-99mDTPA), Tc-99m Di Mercapto Succinic Acid (Tc-99mDMS A), Tc-99m MercaptoAcetylGlycylGlycylGlycine (Technescan MAG3) and Tc-99m-EC (Technetium labeled di-cysteine, Tc-99m-EC). Currently an estimated 70% of all the renal scans in the United States are performed with Tc-99 mMAG3 and 131I-OIH has been withdrawn from the market even though it had a higher extraction fraction than Tc-99 mMAG3, solely due to high radiation dose and scatter of the images. Nevertheless, despite of improved image quality and diagnostic superiority to Tc-99 mMAG3 still it has limitations. A small percentage of Tc-99 mMAG3 is eliminated via the hepatobiliary pathway, and this percentage increases in patients with impaired renal function; the resulting activity in the gallbladder has been mistaken for activity in the kidney. A larger issue is the fact that the clearance of Tc-99 mMAG3 is suboptimal and is only 50%-60% of the clearance of 131I-OIH. Another reported problem is the reproducibility of the Tc-99 mMAG3 clearance based on plasma sample measurements (Andrew T. Taylor et al., J. Nucl. Med. 2010, 51, 391-396).
Hence, these radiopharmaceutical agents are suboptimal in determining the kidney function, because of high radiation, low resolution and low sensitivity due to re-absorption and this would in turn lead to false positives and false negatives making it difficult for correct diagnoses. At present there is no ideal agent for diagnosing and monitoring kidney function with quantitative extraction efficiency measuring effective Renal Plasma Flow (eRPF) solely by tubular secretion.
Thus, there is an urgent unmet medical diagnostic need to design and develop new unequivocally MAG-3 replacement agents for kidney function determination solely by renal tubular secretion alone.
The technical problem to be solved according to the present invention may therefore be seen in providing novel 18F-labeled pharmaceutical compounds for diagnosing and monitoring kidney function accurately.